title: Early and late renal adverse effects after potentially nephrotoxic treatment for childhood cancer.
abstract: BACKGROUND
  Great improvements in diagnostics and treatment for malignant disease in childhood have led to a major increase in survival. However, childhood cancer survivors (CCS) are at great risk for developing adverse effects caused by multimodal treatment for their malignancy. Nephrotoxicity is one of these known (acute) side effects of several treatments, including cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy, and can cause glomerular filtration rate impairment, proteinuria, tubulopathy and hypertension. However, evidence about the long-term effects of these treatments on renal function remains inconclusive. To reduce the number of (long-term) nephrotoxic events in CCS, it is important to know the risk of, and risk factors for, early and late renal adverse effects, so that ultimately treatment and screening protocols can be adjusted.
  
  
  OBJECTIVE
  To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of and associated risk factors for renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with healthy controls or CCS treated without potentially nephrotoxic treatment.
  
  
  METHODS
  We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2011), MEDLINE/PubMed (from 1945 to December 2011) and EMBASE/Ovid (from 1980 to December 2011).
  
  
  METHODS
  With the exception of case reports, case series and studies including fewer than 20 participants, we included studies with all study designs that reported on renal function (one year or longer after cessation of treatment) in children and adults who were treated for a paediatric malignancy (aged 18 years or younger at diagnosis) with cisplatin, carboplatin, ifosfamide, radiation including the kidney region and/or a nephrectomy.
  
  
  METHODS
  Two review authors independently performed study selection, risk of bias assessment and data extraction using standardised data collection forms. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
  
  
  RESULTS
  The search strategy identified 5504 studies, of which 5138 were excluded on the basis of title and/or abstract. The full-text screening of the remaining 366 articles resulted in the inclusion of 57 studies investigating the prevalence of and sometimes also risk factors for early and late renal adverse effects of treatment for childhood cancer. The 57 studies included at least 13,338 participants of interest for this study, of whom at least 6516 underwent renal function testing. The prevalence of renal adverse effects ranged from 0% to 84%. This variation may be due to diversity in included malignancies, prescribed treatments, reported outcome measurements and the methodological quality of available evidence.Chronic kidney disease/renal insufficiency (as defined by the authors of the original studies) was reported in 10 of 57 studies. The prevalence of chronic kidney disease ranged between 0.5% and 70.4% in the 10 studies and between 0.5% and 18.8% in the six studies that specifically investigated Wilms' tumour survivors treated with a unilateral nephrectomy.A decreased (estimated) glomerular filtration rate was present in 0% to 50% of all assessed survivors (32/57 studies). Total body irradiation; concomitant treatment with aminoglycosides, vancomycin, amphotericin B or cyclosporin A; older age at treatment and longer interval from therapy to follow-up were significant risk factors reported in multivariate analyses. Proteinuria was present in 0% to 84% of all survivors (17/57 studies). No study performed multivariate analysis to assess risk factors for proteinuria.Hypophosphataemia was assessed in seven studies. Reported prevalences ranged between 0% and 47.6%, but four of seven studies found a prevalence of 0%. No studies assessed risk factors for hypophosphataemia using multivariate analysis. The prevalence of impairment of tubular phosphate reabsorption was mostly higher (range 0% to 62.5%; 11/57 studies). Higher cumulative ifosfamide dose, concomitant cisplatin treatment, nephrectomy and longer follow-up duration were significant risk factors for impaired tubular phosphate reabsorption in multivariate analyses.Treatment with cisplatin and carboplatin was associated with a significantly lower serum magnesium level in multivariate analysis, and the prevalence of hypomagnesaemia ranged between 0% and 37.5% in the eight studies investigating serum magnesium.Hypertension was investigated in 24 of the 57 studies. Reported prevalences ranged from 0% to 18.2%. A higher body mass index was the only significant risk factor noted in more than one multivariate analysis. Other reported factors that significantly increased the risk of hypertension were use of total body irradiation, abdominal irradiation, acute kidney injury, unrelated or autologous stem cell donor type, growth hormone therapy and older age at screening. Previous infection with hepatitis C significantly decreased the risk of hypertension.Because of the profound heterogeneity of the studies, it was not possible to perform any meta-analysis.
  
  
  CONCLUSIONS
  The prevalence of renal adverse events after treatment with cisplatin, carboplatin, ifosfamide, radiation therapy involving the kidney region and/or nephrectomy ranged from 0% to 84%. With currently available evidence, it was not possible to draw any conclusions with regard to prevalence of and risk factors for renal adverse effects. Future studies should focus on adequate study design and reporting and should deploy multivariate risk factor analysis to correct for possible confounding. Until more evidence becomes available, CCS should be enrolled into long-term follow-up programmes to monitor their renal function and blood pressure.
authors.affiliation: Medical Informatics, Academic Medical Center, P.O. Box 22660, Amsterdam, Netherlands, 1100 DD.
authors.forename: Sebastiaan L
authors.initials: SL
authors.lastname: Knijnenburg
authors.forename: Renée L
authors.initials: RL
authors.lastname: Mulder
authors.forename: Antoinette Y N
authors.initials: AY
authors.lastname: Schouten-Van Meeteren
authors.forename: Arend
authors.initials: A
authors.lastname: Bökenkamp
authors.forename: Hester
authors.initials: H
authors.lastname: Blufpand
authors.forename: Eline
authors.initials: E
authors.lastname: van Dulmen-den Broeder
authors.forename: Margreet A
authors.initials: MA
authors.lastname: Veening
authors.forename: Leontien C M
authors.initials: LC
authors.lastname: Kremer
authors.forename: Monique W M
authors.initials: MW
authors.lastname: Jaspers
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016190:Carboplatin / Q000009:adverse effects; D002648:Child; D002945:Cisplatin / Q000009:adverse effects; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000209:etiology; D017674:Hypophosphatemia / Q000453:epidemiology / Q000209:etiology; D007069:Ifosfamide / Q000009:adverse effects; D008275:Magnesium Deficiency / Q000453:epidemiology / Q000209:etiology; D009392:Nephrectomy / Q000009:adverse effects*; D011507:Proteinuria / Q000453:epidemiology / Q000209:etiology; D011878:Radiotherapy / Q000009:adverse effects*; D051436:Renal Insufficiency, Chronic / Q000453:epidemiology / Q000209:etiology*; D012307:Risk Factors; D017741:Survivors
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin; D007069:Ifosfamide